Ciliary neurotrophic factor protects SH-SY5Y neuroblastoma cells against Aβ1-42-induced neurotoxicity via activating the JAK2/STAT3 axis
Ciliary neurotrophic factor protects SH-SY5Y neuroblastoma cells against Aβ1-42-induced neurotoxicity via activating the JAK2/STAT3 axis
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DOI：
10.5114/fn.2015.54423
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发表时间：
2015-01-01
影响因子：
2
通讯作者：
Zhou, Fanfan
中科院分区：
文献类型：
--
作者：
Wang, Ke;Xie, Minhao;Zhou, Fanfan
聚集的淀粉样蛋白β（A β）的神经毒性已被认为是阿尔茨海默病（AD）发病机制中的关键原因，其通过诱导氧化应激并因此触发细胞凋亡而导致神经元细胞损伤。最近发现Janus酪氨酸激酶2/信号转导子和转录激活子3（JAK 2/STAT 3）信号通路的β依赖性失活在AD相关的记忆障碍中起关键作用。以往的研究表明，A β诱导神经元产生异常活性氧（reactive oxygen species，ROS）可能是导致JAK 2/STAT 3轴失活的原因。由于JAK 2/STAT 3轴是睫状神经营养因子（CNTF）介导的神经保护活性的主要转导子，因此本研究广泛评估了CNTF激活JAK 2/STAT 3轴是否是该蛋白对A β（1-42）诱导的细胞毒性、氧化损伤和人SH-SY 5 Y神经母细胞瘤细胞凋亡的神经保护作用的原因。我们的数据显示，CNTF可以通过激活JAK 2/STAT 3信号通路减轻或恢复A β（1-42）诱导的人SH-SY 5 Y神经母细胞瘤细胞的细胞损伤。此外，CNTF显著阻止A β（1-42）诱导的线粒体功能障碍和丝裂原活化蛋白激酶（MAPK）的激活，这种作用可以被特异性JAK 2抑制剂AG 490有效减弱。总之，这项研究证实了CNTF对A β（1-42）诱导的人SH-SY 5 Y神经母细胞瘤细胞细胞毒性事件的保护作用的详细机制-这些信息可能有助于更好地理解CNTF的作用机制，并为AD治疗提供新的靶点
The neurotoxicity of aggregated amyloid beta (A beta) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD), which leads to neuronal cell damage by inducing oxidative stress and consequently triggering cell apoptosis. Recently, A beta-dependent inactivation of the Janus tyrosine kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was found to play a critical role in the memory impairment related to AD. Previous research indicated that JAK2/STAT3 axis inactivation might be the result of aberrant reactive oxygen species (ROS) generation induced by A beta in neurons. As the JAK2/STAT3 axis is a major transducer of ciliary neurotrophic factor (CNTF)-mediated neuroprotective activity, this study extensively evaluated whether activation of the JAK2/STAT3 axis by CNTF was responsible for the neuroprotective effect of this protein against A beta(1-42)-induced cytotoxicity, oxidative injury and cell apoptosis in human SH-SY5Y neuroblastoma cells. Our data showed that CNTF could attenuate or restore cell injury induced by A beta(1-42) in human SH-SY5Y neuroblastoma cells through activating the JAK2/STAT3 signaling pathway Furthermore, CNTF strikingly prevented A beta(1-42)-induced mitochondria( dysfunction and activation of mitogen-activated protein kinases (MAPKs), an effect that could be potently attenuated by the specific JAK2 inhibitor AG490. In summary, this study confirmed the detailed mechanism accounting for CNTF's protective effect against A beta(1-42)-induced cytotoxic events in human SH-SY5Y neuroblastoma cells - information which might significantly contribute to better understanding of the mechanism of action of CNTF as well as providing a novel target in AD therapy